The Role of Nicotinamide Phosphoribosyltransferase in Cerebral Ischemia

Abstract

Recombinant tissue plasminogen activator is the only drug approved for the clinical treatment of acute ischemic stroke. Thus, there is an urgent unmet need for novel stroke treatments. Endogenous defense mechanisms against stroke may hold the key to new therapies for stroke. A large number of studies suggest that nicotinamidephosphoribosyl-transferase (NAMPT) is an attractive candidate to improve post-stroke recovery. As a multifunctional protein, NAMPT plays important roles in immunity, metabolism, aging, inflammation, and stress responses. NAMPT exists in both the intracellular and extracellular space. As a rate-limiting enzyme, intracellular form (iNAMPT) catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. iNAMPT closely regulates energy metabolism, enhancing the proliferation of endothelial cells, inhibiting apoptosis, regulating vascular tone, and stimulating autophagy in disease conditions such as stroke. Extracellular NAMPT (eNAMPT) is also known as visfatin (visceral fat–derived adipokine) and has pleotropic effects. It is widely believed that the diverse biological functions of eNAMPT are attributed to its NAMPT enzymatic activity. However, the effects of eNAMPT on ischemic injury are still controversial. Some authors have argued that eNAMPT exacerbates ischemic neuronal injury non-enzymatically by triggering the release of TNF-α from glial cells. In addition, NAMPT also participates in several pathophysiological processes such as hypertension, atherosclerosis, and ischemic heart disease. Thus, it remains unclear under what conditions NAMPT is beneficial or destructive. Recent work using in vitro and in vivo genetic/pharmacologic manipulations, including our own studies, has improved our understanding of NAMPT. This review focuses on the multifaceted and complex roles of NAMPT under normal and ischemic conditions.

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

“…iNAMPT over-expression as well as increased circulating levels of eNAMPT were documented in metabolic/inflammatory conditions including obesity, type 2 diabetes, metabolic syndromes, atherogenic inflammatory diseases, therefore supporting a role for eNAMPT as a potential biomarker of cardio-cerebro-vascular disorders (157)(158)(159)(160). Enhanced eNAMPT levels are also described in kidney transplantation recipients (161), polycystic ovary syndrome (162), preeclampsia (163), and acute coronary syndrome (158,164).…”

Hyperbaric Oxygen Reduces Infarction Volume and Hemorrhagic Transformation Through ATP/NAD + /Sirt1 Pathway in Hyperglycemic Middle Cerebral Artery Occlusion Rats

“…Nicotinamide adenine dinucleotide (NAD + ) is a classic energy metabolite that synthesized from its precursors (nicotinic acid and nicotinamide) by the rate-limiting enzyme nicotinamide phosphoribosyl transferase (NAMPT) 11, 12 . NAD + positively regulates the activity of silent mating type information regulation 2 homolog 1 (Sirt1), and plays critical roles in neuroprotection after ischemic stroke 13 .…”

Nampt promotes fibroblast extracellular matrix degradation in stress urinary incontinence by inhibiting autophagy

“…Previous studies have also suggested that Nampt can influence autophagy [ 13 , 14 ], while changes in autophagy levels are known to affect ECM metabolism [ 16 , 35 ]. Therefore, we speculated that Nampt affected ECM metabolism by modulating autophagy, and subsequently examined the effects of Nampt on autophagy.…”

“…Accordingly, we hypothesized that Nampt might affect ECM degradation of SUI fibroblasts. It is also noteworthy that Nampt is implicated in various immune conditions and nerve injuries due to its ability to manipulate apoptosis, metabolic activities, and autophagy [ 13 ]. Similarly, another study documented that inhibition of Nampt led to attenuation of inflammatory symptoms in sepsis by virtue of enhancing autophagy [ 14 ].…”